Highlights from Recent Cancer Literature
Journal: Cancer Research (2014)

Xu and colleagues show that KrasG12D drives lung adenocarcinoma in a specific subset of alveolar type II cells, but induces hyperplasia in bronchioalveolar ducts. They speculate that Notch signaling is responsible for this differential response. Inhibition of Notch activity suppressed Kras-driven adenocarcinoma in the alveolar type II cells, but induced squamous hyperplasia throughout the bronchioalveolar airways. Coactivation of Notch and Kras resulted in papillary adenocarcinoma throughout the bronchioles. Consistent with Notch expression being negatively controlled by direct Sox2 binding to the Notch promoter, overexpression of Sox2 led to downregulation of Notch expression, with decreased expression of Sox2 in a KrasG12D background leading to papillary adenocarcinoma. Thus, the tumor type originating from KrasG12D expression in the lung is dependent on Notch activity, regulated by Sox2 modulated expression of Notch transcription.Xu X, Huang L, Futtner C, Schwab B, Rampersad RR, Lu Y, et al. The cell of origin and subtype of K-Ras-induced lung tumors are modified by Notch and Sox2. Genes Dev 2014;28:1929–39.Aceto and colleagues demonstrate that oligoclonal clusters of circulating tumor cells (CTC) are extremely efficient in metastasis formation despite being present at much lower frequency than individual CTCs in animal models. In addition, prostate and breast cancer patients with detectable CTC clusters showed poorer survival than those patients with single CTCs or with no detectable CTCs. By single-cell RNA sequencing of single CTCs and CTC clusters from patients with metastatic breast cancer, both the cell junction component plakoglobin and multiple components of both desmosomes and adherence junctions were highly differentially expressed. Clusters in breast cancer cell lines were maintained via plakoglobin-dependent cell–cell adhesion in vitro, with loss of plakoglobin in mouse tumor models, reducing metastatic dissemination. These results challenge the prevailing view of epithelial–mesenchymal transition and cell–cell junction disassembly as prerequisites for cancer dissemination. In addition, CTC clusters could potentially be targeted therapeutically through disruption of cell–cell junctions.Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, et al. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 2014;158:1110–22.Transcriptional subprograms regulated by RNA binding proteins that control posttranscriptional gene expression and distinct phenotypes have long been known to be embedded in transcriptional programs. Goodarzi and colleagues identify GC-rich structural cis-regulatory RNA elements, termed sRSEs (structural RNA stability elements). The RNA binding protein TARBP2 binds these elements. This protein is upregulated in breast cancers with poor prognosis and appears to destabilize the mRNAs for at least two transcripts, amyloid precursor protein (APP) and the transcription factor ZNF395. While exact mechanisms by which APP and ZNF395 suppress metastasis are unknown, they seem to limit the invasive and experimental metastasis capacities of MDA-MB-231 cells. The ability of TARBP2 to bind and destabilize specific transcripts was sequence and mRNA structure dependent, suggesting such complexes might be targeted to allow the stabilization of programs that suppress cancer progression.Goodarzi H, Zhang S, Buss CG, Fish L, Tavazoie S, Tavazoie SF. Metastasis-suppressor transcript destabilization through TARBP2 binding of mRNA hairpins. Nature 2014;513:256–60.Polyinosine-polycytidylic acid [pIC] is a synthetic dsRNA mimic that enhances the immune system in an IFN-dependent manner and has been tested in multiple clinical trials. Bhoopathi and colleagues demonstrate that delivery of [pIC] into the cytosol using polyethylenimine ([pIC]PEI) selectively promotes pancreatic cancer apoptosis without affecting normal pancreatic epithelial cells. [pIC]PEI suppressed XIAP and survivin expression and activated an immune response by inducing MDA5 (IFIH1), RIGI (DDX58), and NOXA (PMAIP1) exclusively in pancreatic cancer cells. Further, AKT phosphorylation was inhibited by [pIC]PEI in pancreatic cancer, and this process was central for inducing apoptosis through XIAP and survivin degradation. In vivo administration of [pIC]PEI inhibited pancreatic tumor growth via AKT-mediated XIAP degradation in both subcutaneous and quasi-orthotopic animal models. Taken together, these results offer a preclinical proof-of-concept for the evaluation of [pIC]PEI as an “immunochemotherapy” approach to treat pancreatic cancer.Bhoopathi P, Quinn BA, Gui Q, Shen X-N, Grossman SR, Das SK, et al. Pancreatic cancer-specific cell death induced in vivo by cytoplasmic-delivered polyinosine-polycytidylic acid. Cancer Res; Published OnlineFirst September 9, 2014; doi:10.1158/0008-5472.CAN-14-0819.Winter and colleagues performed an insertional mutagenesis screen to clarify mechanisms of efficacy for the inhibitor YM155, which they characterize as a DNA intercalating agent able to induce apoptotic cell death. Insertions were identified in a single gene, encoding a 35F solute carrier protein (SLC35F2), which facilitates nucleotide sugar transport across membranes. SLC35F2 conferred an increase in intracellular YM155 levels in a dose-dependent manner, suggesting a role in drug uptake. Importantly, YM155 sensitivity was reduced by mutating SLC35F2, with SLC35F2 expression restoring YM155 sensitivity to resistant cells. SLC35F2 expression levels varied across cell lines, correlating with levels and efficacy of YM155, and with general DNA damage response. An understanding of how therapeutic agents cross membranes is critical for cancer therapy and, while the normal function for SLC35FC is unknown, it may be an important biomarker for YM155 efficacy.Winter GE, Radic B, Mayor-Ruiz C, Blomen VA, Trefzer C, Kandasamy RK, et al. The solute carrier SLC35F2 enables YM155-mediated DNA damage toxicity. Nat Chem Biol 2014;10:768–73.Hypermethylation of promoter-associated CpG islands, the CpG island methylator phenotype (CIMP), was first described in colorectal cancer and has subsequently been identified in a broad range of malignancies. High levels of CIMP are common in BRAF- mutant colorectal cancer, resulting in hypermethylation of the MLH1 DNA mismatch repair gene, which in turn destabilizes the genome through altering the length of repeated DNA microsatellite sequences. Through an siRNA screen selecting for reactivation of silenced MLH1, Fang and colleagues identify the transcriptional repressor MAFG as a requirement for MLH1 silencing and CIMP in BRAF-driven colorectal cancer. Extending these results, they also identify a corepressor complex (BACH1, CHD8, and DNMT1) that cooperates in hypermethylation and transcriptional silencing. These studies detail how signaling by a specific oncoprotein can instruct tumor-suppressor gene silencing.Fang M, Ou J, Hutchinson L, Green MR. The BRAF oncoprotein functions through the transcriptional repressor MAFG to mediate the CpG island methylator phenotype. Mol Cell 2014;55:904–15.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.